Abstract: Type 2 diabetes involves aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and resultant pancreatic amyloid deposits. Curcumin, a biphenolic small molecule, has offered potential benefits in other protein misfolding diseases, such as Alzheimer's disease. Our aim was to investigate whether curcumin alters h-IAPP misfolding and protects from cellular toxicity at physiologically relevant concentrations. The effect of curcumin on h-IAPP misfolding in vitro was investigated by electron paramagnetic resonance spectroscopy, ThT fluorescence and electron microscopy. Our in vitro studies revealed that curcumin significantly reduces h-IAPP fibril formation and aggregates formed in the presence of curcumin display alternative morphology and structure. We then tested a potential protective effect of curcumin against h-IAPP toxicity on β-cells. Micromolar concentrations of curcumin partially protect INS cells from exogenous IAPP toxicity. This protective effect, however, is limited to a narrow concentrat...

Abstract: Serum transthyretin (TTR) levels have been reported to be reduced in Portuguese and Japanese patients with TTR V30M familial amyloidotic polyneuropathy and pre-symptomatic carriers of the allele as well as in the carriers of a number of other mutant TTRs. The only published report of serum TTR levels in Swedish TTR V30M carriers suggested that serum TTR levels were elevated in a small number of cases. Since Swedish V30M carriers have a lower degree of clinical penetrance than those from other countries we wished to determine if the reportedly elevated serum TTR concentrations and the lower clinical penetrance were part of a pathologic process that differed between the Swedish carriers and those of other ethnic groups. We compared the serum TTR levels, as determined by ELISA, in 42 documented Swedish TTR V30M carriers with 16 control individuals from the same geographic area in northern Sweden. Serum TTR concentrations in the controls were statistically significantly higher than in the TTR V30M carriers, which were in the same range as those in African-Americans carrying the TTR V122I allele. Thus, Swedish TTR V30M carriers have the same reduction in serum TTR as do other ethnic groups carrying the same or other TTR mutations.

Abstract: We report here two patients with amyloidogenic transthyretin (ATTR) Val30Met familial amyloid polyneuropathy (FAP) who developed numbness in both hands and were diagnosed as having bilateral carpal tunnel syndrome (CTS). In both patients systemic TTR amyloidosis consisting of polyneuropathy affecting both upper and lower limbs and/or autonomic dysfunction gradually appeared after surgery for CTS. Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30Met FAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms. It is also notable that both patients had no genealogical relationship with two Japanese endemic foci of this disease.

Abstract: Congophilic birefringent amyloid deposits, with immunostaining for transthyretin (TTR) and amyloid P, associated with numerous coarse, enlarged and thick elastic fibres, are reported in the stroma of two choroid plexus papillomas, a finding not previously described in choroid plexus tumours. TTR was expressed as aggregates of 'doughnut-shaped' bodies, in which the TTR-positive peripheral area encircled the elastic fibre (TTR-negative core). Ultrastructurally, the amyloid microfibrils surrounded the elastic fibres and appeared to continue into the microfibrillar mantle of the latter. The stromal TTR-amyloid deposits associated with abundant elastic fibres in tumours that occur in the choroid plexus may be related to the alteration (production/accumulation, insufficient breakdown and/or extracellular matrix modifications) of some of the choroid plexus functions (removal, target and source of polypeptides, including TTR synthesis) and may be of interest for future studies on choroid plexus polypeptide activity and on protein development into elastomeric and amyloidogenic microfibrils.

Abstract: Primary bladder amyloidosis is a rare disease. There are approximately 100 reported cases. The lesions can be confused with bladder neoplasm and are characterised histologically by the classical apple green birefringence under polarised light. In this article, we report a 51-year-old lady with known history of primary bladder amyloidosis presenting with gross hydronephrosis 3 years after the first diagnosis. Laparoscopic ileal replacement of bilateral ureters was performed. There was no recurrent ureteric obstruction 2 years after surgery. This case demonstrates the progressive nature of primary amyloidosis of bladder. The diagnosis of primary bladder amyloidosis warrants long-term surveillance of upper urinary tract.

Abstract: We are pleased to announce that Per Westermark, MD, PhD, became the Editor-in-Chief of Amyloid: the Journal of Protein Folding Disorders on 1 July 2010. He succeeds Dr. Alan S. Cohen, who is the fo...

Abstract: The 4th International Symposium on Alzheimer's Disease (AD) and Related Disorders in the Middle East was held October 26–28, 2007 in Athens, Greece. It attracted participants from the United States...

Abstract: Regenerative medicine deals with the possible use of stem cells to repair tissues damaged by aging and related diseases, including amyloidoses. In the latter case, the toxicity of the amyloid deposits can, in principle, question the possibility to graft specific tissues by undifferentiated cells. To assess whether stem cells are vulnerable to amyloid toxicity, we exposed, in culture, murine embryonic stem (ES) cells and haematopoietic progenitor (HP) cells to oligomers of the amyloidogenic peptide Aβ42 at concentrations previously shown to be cytotoxic to several other cell types. These stem cells did not display any sign of apoptosis and their survival, proliferation and differentiation were not affected by the oligomers although the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay revealed that ES, but not HP, cells displayed some impaired ability to reduce the tetrazole salts possibly as a result of transient oxidative stress. Our results support a remarkable resistance of the investigated stem cells against amyloids and hence their potential use in cell therapy of Alzheimer's disease and, possibly, other amyloid diseases.

Abstract: Slowly progressing subcutaneous nodules all over the body were detected in 1994 in an otherwise healthy, now 66-year-old woman (UNK). A first biopsy was taken 10 years ago and revealed amyloid. Immunohistochemistry was suggestive for ALkappa. From a nodular excisate, performed in the same year for cosmetic reasons, amyloid fibrils were extracted. Protein separation according to their size revealed multiple protein fragments below the MW of an intact kappa-light chain. They were identified as kappa-fragments by Western blotting. The kappa-fragments were cleaved into overlapping peptides using tryptic, N-Asp and chymotryptic digests. Peptides were sequenced by Edman-degradation and mass spectrometry. The complete amino acid sequence of the variable region and most of the constant region of ALkappa (UNK) was identified in various fragments comprising positions 1 to 207 of a monoclonal kappa(I)-light chain. Four novel and several rare amino acid exchanges have been identified as compared to 17 amyloidogenic and >100 non-amyloidogenic kappa(I)-sequences published, leading to increased hydrophobicity of ALkappa (UNK). Sequence analysis of C-region peptides allowed one to determine the kappa-allotype as being invb(+). A rabbit antibody was produced against ALkappa(I) (UNK). It strongly reacted with amyloid on formalin-fixed paraffin embedded tissue sections of the same patient and detected ALkappa-amyloid of many other patients. In contrast, antibodies produced against kappaBJP of subclasses kappa(I)-kappa(IV) failed to label ALkappa (UNK) amyloid deposits. The patient continues to be free of systemic disease, already for 14 years until today.

Abstract: Patients with type 2 diabetes have a marked reducedbeta cell mass and fail to produce sufficient amounts of insulin required for regulation of glucose home- ostasis. Recent research supports ...

Abstract: Strengthening the positions of Scandinavian science in research on neurodegenerative and age-dependent amyloid diseases

Abstract: Prof. Dr. Moshe Wolman was one of the pioneers in the modern amyloid histochemistry. He was a member of a small group of distinguished and internationally renowned histochemists. Prof. Wolman had a...

Abstract: Renal artery embolisation (RAE) is an interventional radiology procedure which is used to embolise small branches of renal artery. It is mainly used for urologic purposes, i.e., vascular malformations, angiomyolipomas and renal tumours not amenable to surgical resection. Bilateral RAE can be performed via using absolute ethanol, polyvinyl alcohol or microparticles. After RAE, patients may experience post-embolisation syndrome which is usually self-limited. Use of this procedure for refractory nephrotic syndrome has been rarely defined in the literature to date. Here, we describe a patient who had nephrotic syndrome due to secondary systemic amyloidosis. The patient presented with severe proteinuria (33 g per day), hypoalbuminaemia and anasarca oedema. We applied bilateral RAE with microparticles. We did not observe any complications associated with the procedure. Protein excretion, laboratory values and clinical signs returned to normal.

Abstract: Light chain amyloidosis (AL amyloidosis) is a haematological disorder in which a clonal population of B cells expands and secretes enormous amounts of the immunoglobulin light chain protein. These light chains misfold and aggregate into amyloid fibrils, leading to organ dysfunction and death. We have studied the in vitro fibril formation kinetics of two patient-derived immunoglobulin light chain variable domain proteins, designated AL-09 and AL-103, in response to changes in solution conditions. Both proteins are members of the κI O18:O8 germline and therefore are highly similar in sequence, but they presented with different clinical phenotypes. We find that AL-09 forms fibrils more readily and more rapidly than AL-103 in vitro, mirroring the clinical phenotypes of the patients and suggesting a possible connection between the fibril kinetics of the disease protein and the disease progression.

Abstract: Congo red-stained sections of amyloid may show various colours between crossed polariser and analyser. The aims were to see how papers described the colours, to compare descriptions with illustrations, and to explain the colours. In 160 papers on Congo red-stained amyloid, the commonest descriptions were 'green birefringence' and 'apple-green birefringence'. In 191 figures in 82 papers, 59 (31%) showed a pure green colour, 62 (32%) showed green and yellow or blue and yellow, 38 (20%) showed green and a colour other than yellow, mostly red, and 32 (17%) showed other colours. Discrepancies between colours reported and illustrated were noted in 127 figures (66%). Most (77) were between green alone in descriptions and green and another colour in figures, and 30 were between green in descriptions and no green at all in figures. Pure green can be seen in ideal conditions, but more often there are green and yellow, explained by strain birefringence, and green and red or other combinations, explained by uncrossing of polariser and analyser. These other anomalous colours are just as characteristic of amyloid as the pure green colour. Many papers on Congo red-stained amyloid appear to describe what is expected theoretically rather than what is actually seen.

Abstract: Beta-amyloid (Aβ) is deposited in the parenchyma and blood vessel walls of the senescent brain, and forms lesions termed senile plaques (SPs) and cerebral amyloid angiopathy (CAA). Since in Alzheimer's disease (AD) excessive Aβ is linked to cognitive deterioration, the mechanisms of degradation and clearance of Aβ are now being researched for use in AD therapy. We conducted an immunohistochemical study of the patterns of deposition of two Aβ subtypes (Aβ40 and Aβ42) and the distribution of the Aβ degrading enzyme neprilysin (NEP) in the brains of aged squirrel monkeys, a species known to develop CAA and SPs. Aβ deposits were observed mainly in the cerebral cortex of five older monkeys, and were absent in monkeys under 12 years of age. NEP expression was observed in the caudate nucleus, putamen, globus pallidus, substantia nigra and the molecular layer of the dentate gyrus, and thus exhibited a distribution complementary to those of CAA and SPs in cerebral cortex and hippocampus. It is known that CAA is mo...

Abstract: Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of beta(2)-microglobulin (beta(2)m) into amyloid fibrils (Abeta(2)M). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie Abeta(2)M fibril formation in DRA, we generated transgenic mice that overexpress human beta(2)m protein in a mouse beta(2)m gene knockout background (hB2MTg(+/+) mB2m(+/+)). The hB2MTg(+/+)mB2m(-/-) mice express a high level of human beta(2)m protein in many tissues as well as a high plasma beta(2)m concentration (192.8 mg/L). This concentration is >100 times higher than that observed in healthy humans and >4 times higher than that detected in patients on dialysis. We examined spontaneous and amyloid fibril-induced amyloid deposition in these mice. Amyloid deposition of beta(2)m protein was not observed in aged or amyloid fibril injected animals. However, mouse senile apolipoprotein A-II amyloidosis (AApoAII) was detected, particularly in the joints of mice that were injected with AApoAII amyloid fibrils. This study demonstrates that this mouse model could be valuable in studying the components and conditions that promote DRA, and indicates that high plasma concentrations of hbeta(2)m as well as seeding with pre-existing amyloid fibrils may not be sufficient to induce Abeta(2)M.

Abstract: Aims. To detect cardiac amyloidosis (CA) earlier, it is inevitable to improve diagnostic strategies.Methods and results. The impact of ECG, echocardiography including tissue Doppler imaging (TDI) and strain, and myocardial biopsies was evaluated in 30 patients (63% (n = 19) men, mean age 66 ± 8 years, NYHA 3.0 ± 0.5, 73% with prior myocardial decompensation), in whom we proved CA. Amyloid was confirmed by apple-green birefringence under polarised light, and the causing protein by immunohistochemical examinations. Genetic analyses excluded familial CA. All patients (AL-lambda (n = 22), AL-kappa (n = 3), senile amyloidosis (n = 5)) had echocardiographic signs of restrictive cardiomyopathy (RCM), typical TDI and strain parameters (E'septal; E′ lateral 8; S' ≤9 cm/s; global longitudinal strain (GLS) −7.9 ± 3.8%). Pericardial effusions were present in 63% of patients. ECGs were suspicious in many patients: 19 (63%) had low-voltage, 23 (77%) reduced R waves in V1–V4, and 57% both. Abnormalities...

Abstract: Oral amyloidosis is usually presented in the tongue and is often associated with multiple myeloma. We present three patients with unusual oral manifestations of primary amyloidosis, which to the best of our knowledge have not been previously published. In two cases the oral manifestation was overt at the time of diagnosis and all cases ended in patient mortality. Since these oral manifestations can contribute to the diagnosis of systemic amyloidosis, clinicians should be made aware of them. Future research should assess the significance of oral manifestation as a prognostic indicator.

Abstract: Background: to investigate the vitreous opacity in patients with familial amyloidotic polyneuropathy (FAP) in two major endemic areas, Japan and Sweden. Methods: we obtained clinical data for 90 pa ...

Abstract: Leptomeningeal amyloidosis associated with mutations in transthyretin (TTR) is a rare but fatal form of amyloidosis. Dementia and intracerebral haemorrhage are prominent features of this disease for which no specific therapy is known. In previous studies, we have shown that antisense oligonucleotides (ASOs) specific for human TTR could inhibit hepatic synthesis of TTR in mice transgenic for a human amyloid-associated TTR and may offer a medical means of treating systemic TTR amyloidosis. Parenteral administration of TTR-specific ASO, however, had no effect on the expression of TTR by the choroid plexus, which is believed to be the source of the amyloid protein in patients who have leptomeningeal amyloidosis. In the present study, mice transgenic for the human TTR amyloid-associated mutation Ile84Ser were treated by administration of TTR-specific ASO (50 μg or 75 μg per day) via an osmotic pump into the cerebral ventricular system over a 4-week period. Intraventricular administration of TTR-specific ASO si...

Abstract: A system of amyloid fibril nomenclature based on the chemical identity of the amyloid fibril forming protein is recommended. This system has been in use for approximately 40 years, but current literature remains confused with clinical and histochemical designations used when the amyloid disease processes were poorly understood. To be designated an amyloid fibril protein, the protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarisation microscopy. Furthermore, the protein must have been unambiguously characterised by protein sequence analysis (DNA sequencing in the case of familial diseases). Current nomenclature lists of 27 human and nine animal fibril proteins are provided together with a list of eight inclusion bodies that exhibit some of the properties of amyloid fibrils.